The present invention relates to chemical and/or physical modification of the surface properties of industrially and medically important substrates. In another aspect, the present invention relates to the modification of surface properties for such purposes as providing surfaces with desired characteristics, such as hydrophilicity, lubricity, durability, and uniformity of thickness. In this aspect, the invention relates to such surface modification techniques as chemical derivatization and photoinitiated polymerization.
The chemical modification of surfaces to achieve desired chemical and/or physical characteristics has been previously described. For example, U.S. Pat. Nos. 4,722,906; 4,973,493; 4,979,959; 5,002,582; and 5,512,329 (each of which is commonly owned by the assignee of the invention described herein, and the disclosure of each is incorporated herein by reference), relate to surface modification by the use of latent reactive groups to achieve covalent coupling of reagents such as biomolecules and synthetic polymers to various substrates. The preferred latent reactive group is typically described as a photochemically reactive functional group (xe2x80x9cphotoreactive groupxe2x80x9d). When exposed to an appropriate energy source, a photoreactive group undergoes a transformation from an inactive state (i.e., ground state) to a reactive intermediate capable of forming covalent bonds with appropriate materials.
Such latent reactive groups can be used, for instance, to first derivatize a target molecule (e.g., thermochemically), in order to then photochemically attach the derivatized target molecule to a surface. Such a sequential approach is suitable in many situations, but can lack such attributes as speed, versatility, and ease of use, particularly when used with target molecules that are inherently difficult to first derivatize or under conditions that would result in loss of biological activity.
Latent reactive groups can also be used to prepare photoactivatable heterobifunctional molecules as linking agents, e.g., having a photoreactive group at one end or portion with a thermochemical attachment group at another (see, e.g., the above-captioned ""582 patent, and U.S. Pat. No. 4,309,453, Reiner et al.). Such linking agents can be used to either attach nonreactive compounds to a surface or to prime a relatively inert surface in order to render it reactive upon exposure to suitable actinic radiation.
U.S. Pat. No. 5,414,075 (commonly owned by the assignee of the present invention and incorporated by reference herein), describes the use of linking agents to prime a surface to provide the surface with photoactivatable groups. This patent describes a restrained, multifunctional reagent useful for priming a support surface, or for simultaneous application with a target molecule to a support. Reagents such as those described above, including those described in the ""075 patent, are generally hydrophobic. As a result, they are of relatively low solubility in aqueous systems, thereby often limiting their usefulness in hydrophilic applications.
U.S. Pat. No. 5,714,360, also commonly owned by the assignee of the invention herein described (and incorporated herein by reference), describes a chemical linking agent comprising a di- or higher functional photoactivatable charged compound. The linking agent provides at least one group that is charged under the conditions of use, in order to provide improved water solubility, and two or more photoactivatable groups in order to allow the agent to be used as a linking agent in aqueous systems. In a preferred embodiment, the charged groups include, but are not limited to, salts of organic acids (such as sulfonate, phosphonate, and carboxylate groups), onium compounds (such as quaternary ammonium, sulfonium, and phosphonium groups), and protonated amines, as well as combinations thereof. The photoreactive groups can be provided by two or more radicals of an aryl ketone such as benzophenone.
On a separate subject, common methods of attaching a polymer to a support surface include the attachment of a preformed polymer to a surface, and grafting a polymer to a surface. For instance, Tazuke et al. discuss the modification of polymer surfaces by the use of a grafting technique that involves treating a base polymer (e.g., polypropylene) with a reacting solution that contains sensitizers (e.g., benzophenone) and a selected polymer to be grafted onto the base polymer. xe2x80x9cA Novel Modification of Polymer Surfaces by Photografting,xe2x80x9d Tazuke et al., pp. 217-241, in Modification of Polymers, ACS Symposium Series 121 American Chemical Society, 1980.
On another subject, polymeric photosensitizers for initiating polymerization have been described. See, for instance, xe2x80x9cRadical Polymerization,xe2x80x9d C. H. Bamford, pp. 940-957 in Kroschwitz, ed., Concise Encyclopedia of Polymer Science and Engineering, 1990. In the subsection entitled xe2x80x9cPhotosensitized Initiation: Polymeric Photosensitizers and Photoinitiators,xe2x80x9d the author states that xe2x80x9c[p]olymeric photosensitizers and photoinitiators have been described. Many of these are polymers based on benzophenone, e.g., poly(p-divinylbenzophenone) (DVBP). Such rigid polymers are reported to be effective sensitizers since hydrogen abstraction from the backbone by excited benzophenone is less likely.xe2x80x9d Further, U.S. Pat. No. 4,315,998 (Neckers) describes polymer-bound photosensitizing catalysts for use in the heterogeneous catalysis of photosensitized chemical reactions such as photo-oxidation, photodimerization, and photocycloaddition reactions. The polymer-bound photosensitizing catalysts are insoluble in water and common organic solvents, and therefore can be readily separated from the reaction medium and reaction products by simple filtration.
To the best of Applicants"" knowledge, the art does not teach, nor are there commercial products that involve, the preparation or use of nonpolymeric coating agents that are themselves attached to a surface of an article in order to initiate photopolymerizaton from the surface. Nor are there generally reagents or methods that can be used to modify such surface properties as thickness, lubricity, and stability of coating in a controlled fashion. In contrast, there remains a need for coating agents having improved water solubility, and improved versatility in use. Finally, and in spite of the developments to date, there remains a need for reagents and methods that can be used to improve the initiation of photopolymerization to grow a polymer from a support surface.
The present invention provides a method of using a coating agent to form a polymer layer on a support surface, as well as a method of priming a support surface with the coating agent itself. The invention also provides a surface coated with a polymer layer formed by such a method, as well as a primed support surface coated with the agent itself. A primed coating agent, in turn, can serve as a xe2x80x9clinkingxe2x80x9d agent to covalently or noncovalently attach a polymer layer to the support surface. Further, the invention provides a coating system that includes a coating agent and polymerizable groups as described herein, as well as a group of novel coating agents.
In one aspect, the present invention provides a method of forming a polymer layer on a support surface, the method comprising:
a) providing a support surface;
b) applying to the support surface a coating agent comprising two or more photoreactive species and one or more negatively charged groups, the coating agent selected from:
i) a conjugated cyclic diketone having attached thereto, either directly or indirectly, one or more substituents comprising negatively charged groups, and wherein each ketone group of the diketone is adapted to serve as a photoreactive moiety capable of being activated in order to provide a free radical; and
ii) a nonpolymeric core molecule having attached thereto, either directly or indirectly, one or more substituents comprising negatively charged groups, and two or more photoreactive species, wherein the photoreactive species are provided as discrete photoreactive groups;
wherein the photoreactive species include at least one first photoreactive species adapted, when activated in the presence of the support surface, to attach the coating agent to the surface, and at least one second photoreactive species adapted, when activated in the presence of free radical polymerizable groups, to initiate polymerization of those groups, the second photoreactive species being adapted, in the absence of such free radical polymerizable groups, to revert to a latent reactive state;
c) illuminating the agent upon the support surface under conditions suitable to photochemically attach the coating agent to the surface by means of the first photoreactive species, and to allow the second photoreactive species to remain unbound to the support surface and to revert to their latent reactive state;
d) providing a plurality of molecules bearing free radical polymerizable groups; and
e) illuminating the molecules bearing polymerizable groups in the presence of the coating agent upon the support surface under conditions suitable to activate the reverted second photoreactive species of the coating agent in order to initiate polymerization of the polymerizable groups on the support surface.
The method according to the present invention provides improved control of the coating process and reduces or avoids many of the deficiencies of previous methods, e.g., low reagent solubility, and the effect on the support surface of such factors as storage history, temperature, and humidity. The present invention can also be used to reduce the occurrence of competing polymerization reactions, as between polymerizable groups on the surface and those still in solution, leading to provide increased yield upon the surface.
Various steps of the present method, including illumination to photochemically attach the coating agent to the surface, as well as providing the molecules bearing polymerizable groups, and illumination to activate photoreactive groups (e.g., reverted groups) in order to initiate polymerization, can be performed in any suitable manner, e.g., simultaneously and/or sequentially. Those skilled in the relevant art, given the present description, will also appreciate the manner in which the reaction conditions can be optimized to perform the process either simultaneously or sequentially, as desired.
The first and second photoreactive species of the present coating agent, independently, can be identical or different. Alternatively, a photoreactive species can be provided in the form of a heat activatable group (e.g., an azide group). As used herein, a photoreactive species is a group capable of being activated to form a covalent bond via hydrogen abstraction upon illumination with light of the appropriate wavelength. Such photoreactive species are preferably also capable, if unable to abstract a hydrogen, of reverting to an inactive, or xe2x80x9clatent reactive,xe2x80x9d state. Thus, upon illumination with light of a suitable wavelength, the first photoreactive species are those that covalently bind to the support surface by abstracting a hydrogen from the surface. The second photoreactive species, on the other hand, are those that remain unreacted and thereafter revert to a latent reactive state. The second photoreactive species thereby remain available for initiating polymerization. When the first and second photoreactive species are different, they may, in a preferred embodiment, be activatable by light of different wavelengths, such that light of a particular wavelength will activate the first photoreactive species but not the second, and vice versa.
While not intending to be bound by theory, it would appear that a coating agent of the present invention tends to be of a suitable size and structure to prevent both first and second photoreactive species from attaching to a support surface. In turn, when the first photoreactive species attaches to a support surface, the second photoreactive species are prevented from also attaching to the support surface as a result of the size of the coating agent and the location of the photoreactive species on that agent.
In one embodiment, a coating agent of this invention further comprises one or more optional spacers that serve to attach a core molecule to corresponding photoreactive species, the spacer being selected from radicals with the general formula:
xe2x80x94Oxe2x80x94(CH2)nxe2x80x94,
and
xe2x80x94(C2H4O)mxe2x80x94C2H4Oxe2x80x94,
wherein n is a number greater or equal to 1 and less than about 5, and m is a number greater or equal to 1 and less than about 4.
The method of this invention can be performed using conventional compounds as coating agents, several of which are commercially available, such as anthraquinone and camphorquinone derivatives, e.g., anthraquinone sulfonic acid salt and camphorquinone sulfonic acid salt. Examples of suitable compounds of this type include conjugated cyclic diketones having attached thereto, either directly or indirectly, one or more substituents comprising negatively charged groups, and wherein each ketone group of the diketone is adapted to serve as a photoreactive moiety capable of being activated in order to provide a free radical. In a particularly preferred embodiment, however, certain coating agents of the present invention are believed to be novel in their own right. In one such embodiment, the coating agent comprises a cyclic hydrocarbon core, having attached thereto one or more substituents comprising negatively charged groups, and two or more photoreactive species, wherein the photoreactive species are provided as discrete photoreactive groups.
In any such embodiment, the photoreactive species include at least one first photoreactive species adapted, when activated in the presence of the support surface, to attach the coating agent to the surface, and at least one second photoreactive species adapted, when activated in the presence of free radical polymerizable groups, to initiate polymerization of those groups, the second photoreactive species being adapted, in the absence of such free radical polymerizable groups, to revert to a latent reactive state. The second photoreactive species, in turn, can be adapted to serve as photoinitiators, and particularly as initiators for free radical polymerization. The charged groups provide the agent with suitable water solubility to allow the agent to be used in aqueous reaction systems. Particularly preferred coating agents include negatively charged groups suitable to provide improved biocompatability and hemocompatability.
In a particularly preferred embodiment, the coating agent is selected from the compounds listed below:
A coating agent of the invention has broad applicability, particularly since it can be used in surface modification reaction systems where previous agents have not been effective. In particular, the presence of one or more charged groups (e.g., salts of sulfonic, carboxylic and phosphoric acids) provides the agent with enhanced water solubility. This, in turn, allows the coating agent to be used in reaction systems favoring water soluble agents. A coating agent of the present invention thereby provides an improved combination of such properties as coating density and structural stability, allowing the agent to be used in a broad range of reaction systems.
Moreover, the presence of photoreactive species permits the agent to be used with a wide variety of support surfaces. The coating agent can be used alone as a coating composition for a support surface, in order to provide a surface primed with the coating agent itself. In this embodiment, the coating agent provides the surface with desirable properties of the coating agent itself, such as, for example, antithrombogenicity, lubricity, hemocomopatability, wettability/hydrophilicity, durability of attachment to the surface, biocompatability, and bacterial adhesion. Alternatively, the coating agent can be used to form a polymer layer upon the support surface. In the latter instance, the coating agent serves as a xe2x80x9clinkingxe2x80x9d agent to covalently or noncovalently attach the polymer layer to the support surface.
In another aspect, the present invention provides a coating system comprising:
1) a coating agent as described herein, and
2) a plurality of molecules bearing polymerizable groups.
In a preferred embodiment, the molecules bearing polymerizable groups are selected from monomeric polymerizable molecules and macromeric polymerizable molecules, the monomers or macromers being either inherently hydrophilic or readily modified (e.g., by hydrolysis or solubilization) to provide hydrophilic characteristics. Such hydrophilic characteristics provide the molecules with an affinity for water, allowing the molecules to be water soluble for processing.
The present invention can be used to provide improved control over the polymerization process as compared to previous methods. This is a result of the use of photoreactive species capable of serving as a photoinitiator (e.g., photoinitiating groups) to initiate polymerization. As described herein, photoinitiating groups are provided by the coating agent itself, instead of being separately provided either in solution or by a preformed polymer to be attached to the support surface. The photoinitiating groups of the present invention are adapted to regeneratively participate in the polymerization process. In a particularly preferred embodiment, the photoreactive species are adapted to undergo reversible photolytic homolysis, thereby permitting photoreactive species that are not consumed in attachment to the support surface to revert to an inactive, or xe2x80x9clatentxe2x80x9d state. These photoreactive species can be subsequently activated, in order to serve as photoinitiator groups for initiating free radical polymerization. Thus, excitation of the photoinitiator is reversible and the group can return to a ground state energy level upon removal of the energy source. Particularly preferred photoinitiators are those groups that are subject to multiple activation in aqueous systems and hence provide increased coating efficiency.
In one embodiment, the coating agent can be applied to a support surface through activation of the first photoreactive species, thereby providing a primed surface comprising the support having a coating agent attached thereto. The primed surface can be illuminated to activate the second photoreactive species in the presence of molecules bearing polymerizable groups. The second photoreactive species serve as photoinitiators for free radical polymerization of the polymerizable groups of the molecules. In this embodiment, the coating agent functions to attach the resulting polymer layer to a support surface, with the polymer grown in situ upon the coating agent layer.
A coating agent of the present invention is preferably selected from the group anthraquinone sulfonic acid salt, camphorquinone sulfonic acid, hydroquinone monosulfonic acid derivatives, 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid dipotassium salt, and 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid dipotassium salt. The resulting polymer layer of the present invention provides an optimal combination of such properties as uniformity of thickness, lubricity, hemocompatability, wettability/hydrophilicity, durability of the coating agent attachment, biocompatability, and bacterial adhesion.
The present invention provides a method of forming a polymer layer on a support surface, the method comprising providing a support surface, applying to the support surface a coating agent comprising two or more photoreactive species and one or more negatively charged groups, illuminating the agent upon the support surface to photochemically attach the coating agent to the surface, providing a plurality of molecules bearing free radical polymerizable groups, and illuminating the molecules bearing polymerizable groups and the coating agent upon the support surface to initiate polymerization of the molecules bearing polymerizable groups on the support surface.
In one aspect, the present invention provides a coating agent comprising a nonpolymeric core molecule having attached thereto, either directly or indirectly, one or more substituents comprising negatively charged groups, and two or more photoreactive species, wherein the photoreactive species are provided as discrete photoreactive groups. In accordance with the invention, the photoreactive species comprise one or more first photoreactive species adapted to attach the coating agent to a surface, and one or more second photoreactive species adapted to initiate photopolymerization.
In one embodiment, the coating agent comprises a conjugated cyclic diketone having attached thereto, either directly or indirectly, one or more substituents comprising negatively charged groups, and wherein each ketone group of the diketone is adapted to serve as a photoreactive moiety capable of being activated in order to provide a free radical. Preferably, the conjugated cyclic diketone is a quinone selected from substituted and unsubstituted benzoquinone, camphorquinone, naphthoquinone, and anthraquinone.
In another embodiment, coating agents of this invention are believed to be novel in their own right and comprise a nonpolymeric core molecule having attached thereto, either directly or indirectly, one or more substituents comprising negatively charged groups, and two or more photoreactive species, wherein the photoreactive species are provided as discrete photoreactive groups. In a preferred embodiment, such coating agents are selected from the group 4,5-bis(4-benzoylphenyhnethyleneoxy)benzene-1,3-disulfonic acid dipotassium salt (DBDS), 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,4-disulfonic acid dipotassium salt (DBHQ), a hydroquinone derivative, an anthraquinone derivative, and a camphorquinone derivative. Optimally, the coating agent is selected from DBDS, DBHQ, and 2,5-bis(4-benzoylphenylmethyleneoxy)benzene-1-sulfonic acid mono (or di-) sodium salt.
Particularly preferred coating agents are selected from the group 4,5-bis(4-benzoylphenylmethyleneoxy)benzene-1,3-disulfonic acid dipotassium salt (DBDS), and 2,5-bis(4-benzoylphenyhnethyleneoxy)benzene-1,4-disulfonic acid dipotassium salt (DBHQ).
As described herein, the coating agent generally provides a low molecular weight core molecule that provides improved coating density of the agent on a support surface of interest. Moreover, the photoreactive groups provide initiators for photopolymerization, as well as an attachment site for the agent to the surface. Finally, the charged group(s) provide improved properties such as water solubility and hemocompatability. The coating agent is thus capable of a wide variety of uses and avoids many of the limitations found in the prior art.
Suitable core molecules of the present invention include nonpolymeric radicals having a low molecular weight (e.g., 100-1000 MW). Suitable core molecules provide an improved combination of such properties as coating density, structural stability, ease of manufacture, and cost. Further, core molecules can be provided with water soluble regions, biodegradable regions, hydrophobic regions, as well as polymerizable regions. Examples of suitable core molecules include cyclic hydrocarbons, such as benzene and derivatives thereof.
Photoreactive species are defined herein, and preferred species are sufficiently stable to be stored under conditions in which they retain such properties. See, e.g., U.S. Pat. No. 5,002,582, the disclosure of which is incorporated herein by reference. Latent reactive groups can be chosen that are responsive to various portions of the electromagnetic spectrum, with those responsive to ultraviolet and visible portions of the spectrum (referred to herein as xe2x80x9cphotoreactivexe2x80x9d) being particularly preferred.
Photoreactive species respond to specific applied external stimuli to undergo active specie generation with resultant covalent bonding to an adjacent chemical structure, e.g., as provided by the same or a different molecule. Photoreactive species are those groups of atoms in a molecule that retain their covalent bonds unchanged under conditions of storage but that, upon activation by an external energy source, form covalent bonds with other molecules.
The photoreactive species generate active species such as free radicals and particularly nitrenes, carbenes, and excited states of ketones upon absorption of electromagnetic energy. Photoreactive species can be chosen to be responsive to various portions of the electromagnetic spectrum, and photoreactive species that are responsive to e.g., ultraviolet and visible portions of the spectrum, are preferred and can be referred to herein occasionally as xe2x80x9cphotochemical groupxe2x80x9d or xe2x80x9cphotogroup.xe2x80x9d
The photoreactive species in photoreactive aryl ketones are preferred, such as acetophenone, benzophenone, anthraquinone, anthrone, and anthrone-like heterocycles (i.e., heterocyclic analogs of anthrone such as those having N, O, or S in the 10- position), or their substituted (e.g., ring substituted) derivatives. Examples of preferred aryl ketones include heterocyclic derivatives of anthrone, including acridone, xanthone, and thioxanthone, and their ring substituted derivatives. Particularly preferred are thioxanthone, and its derivatives, having excitation energies greater than about 360 nm.
The functional groups of such ketones are preferred since they are readily capable of undergoing the activation/inactivation/reactivation cycle described herein. Benzophenone is a particularly preferred photoreactive moiety, since it is capable of photochemical excitation with the initial formation of an excited singlet state that undergoes intersystem crossing to the triplet state. The excited triplet state can insert into carbon-hydrogen bonds by abstraction of a hydrogen atom (from a support surface, for example), thus creating a radical pair. Subsequent collapse of the radical pair leads to formation of a new carbon-carbon bond. If a reactive bond (e.g., carbon-hydrogen) is not available for bonding, the ultraviolet light-induced excitation of the benzophenone group is reversible and the molecule returns to ground state energy level upon removal of the energy source. Photoactivatible aryl ketones such as benzophenone and acetophenone are of particular importance inasmuch as these groups are subject to multiple reactivation in water and hence provide increased coating efficiency.
The azides constitute a preferred class of photoreactive species and include derivatives based on arylazides (C6R5N3) such as phenyl azide and particularly 4-fluoro-3-nitrophenyl azide, acyl azides (xe2x80x94COxe2x80x94N3) such as benzoyl azide and p-methylbenzoyl azide, azido formates (xe2x80x94Oxe2x80x94COxe2x80x94N3) such as ethyl azidoformate, phenyl azidoformate, sulfonyl azides (xe2x80x94SO2xe2x80x94N3) such as benzenesulfonyl azide, and phosphoryl azides (RO)2PON3 such as diphenyl phosphoryl azide and diethyl phosphoryl azide. Diazo compounds constitute another class of photoreactive species and include derivatives of diazoalkanes (xe2x80x94CHN2) such as diazomethane and diphenyldiazomethane, diazoketones (xe2x80x94COxe2x80x94CHN2) such as diazoacetophenone and 1-trifluoromethyl-1-diazo-2-pentanone, diazoacetates (xe2x80x94Oxe2x80x94COxe2x80x94CHN2) such as t-butyl diazoacetate and phenyl diazoacetate, and beta-keto-alpha-diazoacetates (xe2x80x94COxe2x80x94CN2xe2x80x94COxe2x80x94Oxe2x80x94) such as t-butyl alpha diazoacetoacetate. Other photoreactive species include the diazirines (xe2x80x94CHN2) such as 3-trifluoromethyl-3-phenyldiazirine, and ketenes (xe2x80x94CHxe2x95x90Cxe2x95x90O) such as ketene and diphenylketene.
Upon activation of the photoreactive species, the coating agents are covalently bound to each other and/or to the material surface by covalent bonds through residues of the photoreactive species. Exemplary photoreactive species, and their residues upon activation, are shown as follows.
The coating agents of the present invention can be applied to any surface having carbon-hydrogen bonds, with which the photoreactive species can react to immobilize the coating agents to surfaces. Examples of suitable surfaces are described in more detail below.
Photoinitiator groups useful in the present invention include those that can be used to initiate photopolymerization of polymerizable groups, by a process of free radical generation, to a desired extent and within a desired time frame. Photoinitiators are responsible for producing initiating species by the action of light energy. Free radicals can be produced by intramolecular photocleavage or hydrogen abstraction (e.g., inter- or intramolecular). Thus, according to the present invention, polymerization is generally initiated among macromers or monomers by a light-activated free-radical polymerization initiator. Preferred photoinitiators are photosensitive molecules that capture light energy and initiate polymerization of the molecules bearing polymerizable groups (e.g., macromeric polymerizable molecules or monomeric polymerizable molecules).
Examples of preferred photoinitiators include preferred photoreactive species listed above. The photoinitiator group (i.e., the second photoreactive group) can be identical to, or different from, the first photoreactive group used to attach the coating agent to a support surface. In one embodiment, the first and second photoreactive species are adapted to be independently activated by light of different wavelengths (e.g., ultraviolet light versus visible light).
Upon activation of the photoreactive species in the presence of a support surface, the second photoreactive group(s) remain unbound to the support surface and revert to their inactive state in order to serve as photoinitiator groups. While not intending to be bound by theory, it appears that the ability of a photoreactive group to remain unbound (and hence serve as a photoinitiator) is a factor, at least in part, of various reaction conditions (e.g., time and intensity of illumination wavelength, reagent concentration, etc.) and/or restrictions imposed by the size and/or structure of the coating agent itself. The photoinitiator thus remains available to be subsequently activated by a suitable energy source, and thereby initiate photopolymerization.
Photoinitiation of free radical polymerization in the present invention can take place via various mechanisms, including photochemical intramolecular photocleavage, hydrogen abstraction, and redox reactions. In a particularly preferred embodiment, photoinitiation takes place by hydrogen abstraction from the polymerizable groups.
Intramolecular photocleavage involves a homolytic alpha cleavage reaction between a carbonyl group and an adjacent carbon atom. This type of reaction is generally referred to as a Norrish type I reaction. Examples of molecules exhibiting Norrish type I reactivity and useful in a polymeric initiating system include derivatives of benzoin ether and acetophenone. For example, in a preferred embodiment wherein the coating agent of the present invention is provided in the form of a quinone having adjacent carbonyl groups (e.g., camphorquinone), photoinitiation takes place via intramolecular bond cleavage.
A second mechanism, hydrogen abstraction, can be either intra- or intermolecular in nature. A system employing this mechanism can be used without additional energy transfer acceptor molecules and by nonspecific hydrogen abstraction. However, this system is more commonly used with an energy transfer acceptor, typically a tertiary amine, which results in the formation of both aminoalkyl radicals and ketyl radicals. Examples of molecules exhibiting hydrogen abstraction reactivity and useful in a polymeric initiating system, include analogs of benzophenone and camphorquinone.
A third mechanism involves photosensitization reactions utilizing photoreducible or photo-oxidizable dyes. In most instances, photoreducible dyes are used in conjunction with a reductant, typically a tertiary amine. The reductant intercepts the induced triplet producing the radical anion of the dye and the radical cation of the reductant.
Coating agents of the present invention can be used in any suitable manner, e.g., by simultaneous or sequential attachment of the coating agent and chemical compounds (e.g., molecules bearing polymerizable groups) to a support surface. In a preferred embodiment, the method of this invention involves a two step process, involving sequential steps in which coating agent is first attached to the surface, after which compounds are polymerized thereon using the photoinitator of the attached agent. One advantage of a sequential approach is that photopolymerization of this sort allows the generation of thin polymer layers on the support surface. The resultant polymer layer is typically highly adherent, uniform in thickness, and is highly durable. Moreover, solutions used to form the polymer layer can be applied (e.g., via in solution application, dipping, spray coating, knife coating, and roller coating) to any suitable support surface of any surface morphology. The resultant polymer layer, in turn, can be adapted to cover irregular surfaces as well as smooth, relatively uniform surfaces. The polymerizable species can also be attached to the support surface simultaneously with the coating agent of the present invention, by providing suitable reaction conditions to allow such simultaneous attachment of the coating agent and polymerization of the polymerizable species.
In a particularly preferred embodiment, photoinitiation generates active species such as free radicals and particularly nitrenes, carbenes, and excited states of ketones upon absorption of electromagnetic energy. This excited photoinitiator in turn abstracts hydrogen atoms from available sources in proximity to the photoinitiator, e.g., polymerizable species, applied to the primed surface. This hydrogen abstraction thus generates a free radical site within the polymerizable species from which polymerization can proceed.
A typical free radical polymerization comprises four steps: initiation, propagation, termination, and chain transfer. In initiation, a free radical derived from an initiator adds to a monomer molecule to form an active center. Other initiating reactions include addition to the head of the molecule or hydrogen abstraction, and the reaction mechanism depends upon the structures of the radical and monomer. The propagation or growth reaction consists of the rapid addition of monomer molecules to the radical species. The most common mechanism of propagation occurs in head-to-tail fashion. However, propagation may also occur in head-to-head, tail-to-head, and tail-to-tail modes. In termination, the polymer chain stops growing by the destruction of propagating radicals. Normally, in the absence of species that destroy radicals, chain termination occurs by bimolecular interaction of radicals (e.g., radical combinations or disproportionation).
As used herein, a xe2x80x9cchargedxe2x80x9d group generally refers to a group that is present in ionic form in solution, i.e., carries an electrical charge under the conditions (e.g., pH) of use. The charged groups are present, in part, to provide the compound with desired water solubility. Additionally, such charged groups provide a combination of such desirable characteristics as antithrombogenicity and hemocompatability.
The type and number of charged groups in a preferred coating agent are sufficient to provide the agent with a water solubility (at room temperature and optimal pH) of at least about 0.1 mg/ml, and preferably at least about 0.5 mg/ml, and more preferably at least about 1 mg/ml. Given the nature of the surface coating process, coating agent solubility levels of at least about 0.1 mg/ml are generally adequate for providing useful coatings of target molecules (e.g., polymer layers) on surfaces.
The coating agent of the present application can thus be contrasted with many coating agents in the art, which are typically considered to be insoluble in water (e.g., having a comparable water solubility in the range of about 0.1 mg/ml or less, and more often about 0.01 mg/ml or less). For this reason, conventional coating agents are typically provided and used in solvent systems in which water is either absent or is provided as a minor (e.g., less than about 50% by volume) component.
Examples of suitable charged groups include salts of organic acids (e.g., sulfonate, phosphonate, and carboxylate groups), as well as combinations thereof. A preferred charged group for use in preparing coating agents of the present invention is a sulfonic acid salt, e.g., derivatives of SO3xe2x88x92 in which the counterion is provided by any suitable positively charged species, e.g., as a potassium or sodium ion.
In one embodiment, the coating agent of the present invention further includes optional spacers between the nonpolymeric core molecule and one or more of the photoreactive species. A spacer is provided in situations when it is desired to provide more distance between the photoreactive species and the core molecule. For example, it can be desirable to provide a spacer to avoid steric hindrance that may result between the core molecule and the photoreactive species, thus inhibiting the photoreactive species from forming covalent bonds with a support surface (in terms of the second photoreactive species), or from serving as a photoinitiator for polymerization (in terms of the first photoreactive species).
In one embodiment, the present invention contemplates a system comprising a coating agent as described herein, and a plurality of molecules, each bearing one or more polymerizable groups. In accordance with this embodiment, the photoinitiator group serves to initiate polymerization of the polymerizable groups, thereby forming a polymer layer that is covalently bound to the support surface of a desired article via the coating agent. As used herein, xe2x80x9cpolymerizable groupxe2x80x9d shall generally refer to a group that is adapted to be polymerized by initiation via free radical generation, and more preferably by photoinitiators activated by visible or long wavelength ultraviolet radiation.
Suitable polymerizable compounds can be used to provide polymerization products (e.g., a polymer layer resulting from free radical polymerization) that are either inherently hydrophilic or are capable of being readily modified to provide hydrophilic characteristics at appropriate reaction conditions (e.g., pH). Moreover, the polymerizable groups of such compounds, can include those adapted to participate in free-radical polymerization. Preferred compounds include at least one free-radical polymerizable component (e.g., a vinyl group), and at least one functional group with a high affinity for water. As contemplated by the present invention, such functional groups with a high affinity for water can be negatively charged, positively charged, or electrically neutral.
Suitable polymerizable compounds are selected from monomeric polymerizable molecules (e.g., organic monomers), and macromeric polymerizable molecules (e.g., organic macromers). As used herein, xe2x80x9cmacromerxe2x80x9d shall refer to a macromolecular monomer having a molecular weight of about 250 to about 25,000, and preferably from about 1,000 to about 5,000.
Suitable polymerizable compounds can contain electrically neutral hydrophilic functional units, for example, acrylamide and methacrylamide derivatives. Examples of suitable monomers containing electrically neutral hydrophilic structural units include acrylamide, methacrylamide, N-alkylacrylamides (e.g., N,N-dimethylacrylamide or methacrylamide, N-vinylpyrrolidinone, N-vinylacetamide, N-vinyl formamide, hydroxyethylacrylate, hydroxyethylmethacrylate, hydroxypropyl acrylate or methacrylate, glycerolmonomethacrylate, and glycerolmonoacrylate).
Alternatively, suitable polymerizable compounds containing electrically neutral hydrophilic functional units include molecules whose polymers, once formed, can be readily modified (e.g., hydrolyzed by the addition of ethylene oxide) to provide products with enhanced affinity for water. Examples of suitable monomers of this type include glycidyl acrylate or methacrylate, whose polymers bear epoxy groups that can be readily hydrolyzed to provide glycol structures having a high affinity for water.
Examples of suitable monomeric polymerizable molecules that are negatively charged at appropriate pH levels include acrylic acid, methacrylic acid, maleic acid, fumaric acid, itaconic acid, AMPS (acrylamidomethylpropane sulfonic acid), vinyl phosphoric acid, vinylbenzoic acid, and the like.
Alternatively, suitable monomeric polymerizable molecules that are negatively charged at appropriate pH levels include molecules whose polymers, once formed, can be readily modified (e.g., by hydrolysis via the addition of ethylene oxide) to provide products with enhanced affinity for water. Examples of suitable monomers of this type include maleic anhydride, whose polymers bear anyhdride groups that can be readily hydrolyzed to provide carboxylic acid groups, or can be readily reacted with amines to provide amide/acid structures with high affinity for water, and polymerized vinyl esters.
Examples of suitable monomeric molecules that are positively charged at appropriate pH levels include 3-aminopropylmethacrylamide (APMA), methacrylamidopropyltrimethylammonium chloride (MAPTAC), N,N-dimethylaminoethylmethacrylate, N,N-diethylaminoethylacrylate, and the like.
Alternatively, suitable positively charged monomeric polymerizable molecules include those molecules that can be readily modified (e.g., by hydrolysis via the addition of ethylene oxide) to provide products with enhanced affinity for water as well as a positive charge, e.g., glycidyl methacrylate whose polymeric products can be reacted with amines (e.g., ethylamine), to provide hydroxyamino compounds. In some cases, these materials will contain a structural unit with an inherent positive charge, as for example with fully quaternized ammonium structures. In other cases, the positively charged structural unit will exist at certain pH values, particularly at acidic pH values.
In an alternative embodiment, the polymerizable compounds of the present invention comprise macromeric polymerizable molecules. Suitable macromers can be synthesized from monomers such as those illustrated above. According to the present invention, polymerizable functional components (e.g., vinyl groups) of the macromer can be located at either terminus of the polymer chain, or at one or more points along the polymer chain, in a random or nonrandom structural manner.
The number of free-radical polymerizable groups per molecule can be varied according to the application. For example, it can be preferable to employ a macromer with just one free-radical polymerizable unit. In other instances, however, it can be preferable to employ a macromer with more than one, e.g., two or more polymerizable units per macromer. Additionally, the macromer of the present invention can contain structural features to provide improved affinity for water in a manner typically unavailable in small molecule structures (e.g., hydrophilic poly(ethylene glycol) materials).
Examples of suitable macromeric polymerizable compounds include methacrylate derivatives, monoacrylate derivatives, and acrylamide derivatives. Particularly preferred macromeric polymerizable compounds include poly(ethylene glycol)monomethyacrylate, methoxypoly(ethylene glycol)monomethacrylate, poly(ethylene glycol)monoacrylate, monomethyacrylamidopoly(acrylamide), poly(acrylamide-co-3-methacrylamidopropylacrylamide), poly(vinylalcohol)monomethacrylate, poly(vinylalcohol)monoacrylate, poly(vinylalcohol)dimethacrylate, and the like.
Such macromers can be prepared, for instance, by first synthesizing a hydrophilic polymer of the desired molecular weight, followed by a polymer modification step to introduce the desired level of polymerizable (e.g., vinyl) functional units. For example, acrylamide can be copolymerized with specific amounts of 3-aminopropylmethacrylamide comonomer, and the resulting copolymer can then be modified by reaction with methacrylic anhydride to introduce the methacrylamide functional units, thereby producing a useful macromer for purposes of this invention.
Poly(ethylene glycol) of a desired molecular weight can be synthesized or purchased from a commercial source, and modified (e.g., by reaction with methacrylyl chloride or methacrylic anhydride) to introduce the terminal methacrylate ester units to produce a macromer useful in the process of this invention. Some applications can benefit by use of macromers with the polymerizable units located at or near the terminus of the polymer chains, whereas other uses can benefit by having the polymerizable unit(s) located along the hydrophilic polymer chain backbone.
Such monomeric and macromeric polymerizable molecules can be used alone or in combination with each other, including for instance, combinations of macromers with other macromers, monomers with other monomers, or macromers combined with one or more small molecule monomers capable of providing polymeric products with the desired affinity for water. Moreover, the above polymerizable compounds can be provided in the form of amphoteric compounds (e.g., zwitterions), thereby providing both positive and negative charges.
Coating agents as described herein can be used to modify any suitable surface. Where the latent reactive group of the agent is a photoreactive group of the preferred type, the support surface to be coated preferably provides abstractable hydrogen atoms suitable for covalent bonding with the activated group. In another embodiment, the surface can be modified (e.g., by pretreatment with a suitable reagent) to provide abstractable hydrogen atoms on the surface.
The method according to the present invention is suitable for use in connection with a variety of support surfaces, including hydrogel polymers, silicone, polypropylene, polystyrene, poly(vinyl chloride), polycarbonate, poly(methyl methacrylate), parylene and any of the numerous organosilanes used to pretreat glass or other inorganic surfaces. The photoreactive coating agents can be applied to surfaces in any suitable manner (e.g., in solution or by dispersion), then photoactivated by uniform illumination to immobilize them to the surface. Examples of suitable hydrogel polymers are selected from silicone hydrogels, hydroxyethylmethacrylate polymers, and glyceryl methacrylate polymers.
Other suitable surface materials include polyolefins, polystyrenes, poly(methyl)methacrylates, polyacrylonitriles, poly(vinylacetates), poly(vinyl alcohols), chlorine-containing polymers such as poly(vinyl) chloride, polyoxymethylenes, polycarbonates, polyamides, polyimides, polyurethanes, phenolics, amino-epoxy resins, polyesters, silicones, cellulose-based plastics, and rubber-like plastics. See generally, xe2x80x9cPlastics,xe2x80x9d pp. 462-464, in Concise Encyclopedia of Polymer Science and Engineering, Kroschwitz, ed., John Wiley and Sons, 1990, the disclosure of which is incorporated herein by reference. In addition, supports such as those formed of pyrolytic carbon and silylated surfaces of glass, ceramic, or metal are suitable for surface modification.
Such materials can be used to fabricate a number of devices capable of being provided, either before, during and/or after their fabrication, with a polymer layer according to the present invention. Implant devices are one general class of suitable devices, and include, but are not limited to, vascular devices such as grafts, stents, catheters, valves, artificial hearts, and heart assist devices; orthopedic devices such as joint implants, fracture repair devices, and artificial tendons; dental devices such as dental implants and fracture repair devices; ophthalmic devices such as lenses and glaucoma drain shunts; and other catheters, synthetic prostheses and artificial organs. Other suitable biomedical devices include dialysis tubing and membranes, blood oxygenator tubing and membranes, blood bags, sutures, membranes, cell culture devices, chromatographic support materials, biosensors, and the like.
According to the present invention, surface modification can be achieved using photopolymerization (e.g., by free radical polymerization). In accordance with the present method, a selected surface is contacted with a coating agent, as described above. During and/or after application of the coating agent, the surface is illuminated with UV light of the appropriate wavelength, thereby activating the photoreactive species. The coating agent is thus immobilized to the surface, by means of the first photoreactive species (with the second photoreactive species reverting to inactive form), and excess coating agent can then be optionally washed away, leaving a surface primed with a base layer of coating agent.
The coating agent can be applied to the surface of interest in any suitable manner. For example, the coating agent can be applied by dip coating or by dispersing the agent on the surface (for example, by spray coating). Suitable methods of application include application in solution, dipping, spray coating, knife coating, and roller coating. In a particularly preferred embodiment, the coating agent is applied to the surface via spray coating, as this application method provides increased density of the coating agent on the support surface, thereby improving grafting durability.
In the sequential approach described herein, a solution containing polymerizable compounds can be applied to a primed surface. The solution can be illuminated in situ to activate the second photoreactive group(s) that serve as a photoinitiator(s), thus initiating free radical polymerization via hydrogen abstraction. In a particularly preferred embodiment, photopolymerization takes place in an inert atmosphere, since oxygen interferes with free radical polymerization. Deoxygenation can take place using an inert gas such as nitrogen.
Once the system has been deoxygenated, the surface can again be illuminated with UV light of the appropriate wavelength. This second illumination thus activates the second photoreactive group(s) serving as a photoinitiator(s) of free radical polymerization. In a preferred embodiment, illumination generates the excited state of the photoreactive group, allowing the excited molecule to abstract a hydrogen from available sources, e.g., molecules bearing polymerizable groups. Such hydrogen abstraction generates a free radical site, from which polymerization can proceed.
The invention will be further described with reference to the following non-limiting Examples. It will be apparent to those skilled in the art that many changes can be made in the embodiments described without departing from the scope of the present invention. Thus the scope of the present invention should not be limited to the embodiments described in this application, but only by embodiments described by the language of the claims and the equivalents of those embodiments. Unless otherwise indicated, all percentages are by weight
In one embodiment, the invention provides a coating agent and corresponding method of using to form a polymeric layer on a surface, wherein the coating agent comprises a compound of the formula: 
wherein
X1 comprises a first photoreactive species;
X2 comprises a second photoreactive species;
Y comprises a nonpolymeric core molecule; and
Z comprises at least one charged group.